Gender differences in asthma: unsolved puzzles

Dirkje Postma

University Medical Center Groningen

Groningen Research Institute forAsthma and COPD

The Burden of Asthma: increasing prevalence in children/adolescents

• Asthma is a significant burden not only in terms of health care costs, but also in lost productivity and reduced participation in family and social life

• The prevalence of asthma is increasing worldwide, especially among children

Available at: http://www.ginasthma.com. Slide 21. 2003.

Finland(Haahtela et al)

Sweden(Aberg et al)

Japan (Nakagomi et

al)Scotland

(Rona et al)

UK(Omran et al)

New Zealand(Shaw et al)

Prevalence, %

USA(NHIS)

Australia(Peat et al)

0 5 10 15 20 25 30 35

19921982

19891975

19921982199419891992198219921982

1991197919891966{

{

{

{

{

{

{

{

Asthma: a benign disease?

• sudden attacks of breathlesness and/or cough

• allergy (generally)• reversible airway obstruction • hyperresponsiveness

Age frequent persistent

episodic

7 2.1 3.8

14 2.1 4.0

21 1.5 1.5

28 1.3 1.8

Age and asthma - male : female ratio

Clough Cl Exp All 1993

1979

1.6

1.4

1.2

1.0

MaleFemale

1983 1987 1991 1995 1997

1.8

0.8Rat

e p

er 1

00,0

00 p

opu

lati

on

year

Age-adjusted death rate due to asthma in USAAge-adjusted death rate due to asthma in USA

Source:National Center for Health Statistics

Underdiagnosis in females

-girls

-parents

-doctor

Especially in low-income group

Childhood asthma - boy:girl ratioChildhood asthma - boy:girl ratio

Treatment of asthma: age 7-12

wheeze allergen exercise morning symptoms symptoms tightness

20

40

60

MaleFemale

0Per

cen

tag

e tr

eate

d 80

100

Kuhni et al Ped Pulm 1995

***

Airway obstruction!

Before 10 minutes after allergen inhalation

Sex hormones

• Interaction between sex hormones and immune function

• Women are more susceptible to specific immunological disorders

• Better B cell mediated immunity• Higher Ig levels• Higher CD4 to CD8 ratios

Sex hormones and asthma

• In humans data remain inconclusive• Mouse model:

– Estrogen: increases BALF eosinophilia in oophorectomized rats with asthma (Ligeiro de Oliveira et al. 2004)

– Progesterone: increases airway inflammation in male mice with asthma (Hellings et al. 2003)

– Testosterone: Castration of male asthmatic mice increases BALF eosinophilia (Hayashi et al. 2003)

OVA-specific IgE in serum

PBS OVA PBS OVA0.0

0.5

1.0

1.5

2.0

2.5

|------Male------| |-----Female----|

***

******

Cytokines in lung tissue

IL-5 RANTES

PBS OVA PBS OVA0

500

1000

1500

2000

|------Male------| |-----Female----|

******

PBS OVA PBS OVA0

100

200

300

|------Male------| |-----Female----|

**

Post-hoc analysis: ** p<0.01 *** p<0.001

- -

Barnes PJ

Chronic inflammation

Structural changes

Acuteinflammation

Steroidresponse

Time

Progression of asthma into (partial) irreversible airway obstruction

Airway Branching Morphogenesis

MMPS & ADAMs

Growth factors

Lung growth in childrenLung growth in children

girls have larger airways in proportion to lung

volume than boys

puberty2 2 years

Males Females

CC CT TT CC CT TT

-60

-50

-40

-30

-20

-10

0

10

20p=0.01p=0.04

nsns

Exon 1 +30 T/C

Mea

n a

nn

ual

dec

line

in F

EV

1

(ml/y

ear)

19 35 18 10 29 9n=

Genotype ESR1 and lung function decline

Dijkstra et al J All CLin Imm 2006

Gender effect of inhaled corticosteroids?

Convery et al ERJ 2000

0.5

1.5

2.0

0

2.5

1.0

Male Female

Doubling dose increase in PD20 methacholine

*

-50

-40

-30

-20

-10

0

Mean annual FEV1 decline in asthma

Inhaled steroids

- + - +

P < 0.01

Dijkstra et al 2005 submitted

male

female

less prevalent in girlsmore prevalent in female adults

due to • airway and lung growth • hormonal changes• hyperresponsiveness• immune development

Conclusions on asthma

In females• more severe • higher mortality• more and longer hospitalisations (except boys)

• less response to inhaled steroids?• different interaction with genetic background?• hormonal influence?

Conclusions on asthma